Tertiary amine derivatives of nu-and omicron-saccharin



United States Patent Ice Patented $2, 1 55 2,751,392 TERTIARY AMINE DERIVATIVES or N- AND O-SACCHARIN R Charles H. Grogan, Falls Church, Va., and Leonard M. N Rice, Baltimore, Md., assignors to Geschickter Fund for 50/ Medical Research, Inc., New York, N. Y., a c'orporation of New York No Drawing. Application November 23, 1953, In these formulae, x represents a number from 2 to 6 Serial 4 and -R represents an alkyl group having from 1 to 6 carbon 7 Claims. (Cl. 260-301) atoms, or the grouping This invention relates to compositions of matter, particularly to chemotherapeutic organic compounds and methods of their preparation and more particularly to R compounds useful as analgesic and antihistaminic agents may represent a heterocyclic ring system such as pyr.

in m u p rolidine, morpholine and piperidine.

Specifically, the lnventlon Involves the discovery and Formula 1(a) Shows h y of compound d ri bl c n e p the dlsdosufe of novel types of eerhpouhds from linkage of the side chain to the 'saccharin nucleus hereinafter referred to as the N- and O- saccharm derivathrough an ether l k; Formula v1 1 h type b i bl tives, the parent bases, slmple salts, and quaternary salts 20 by substituting on the imide nitrogen; and F l 1( th the type obtainable by linkage through an amino group These novelcompounds possess umque solublhty charto the carbon adjacent to the i id ni aot l w, which 13 unusual 111 the Whole elass of se The first class of saccharin derivatives, i. e., those repcharln Compounds except for the sodlhm salt- The resented by Formula 1(a), are obtained by reacting equihi e lic arsi h ft z l fli l tgd s i f so l iib le ih ig gg lecular amounts of pseudo saccharin chloride with the s desired amino alcohol in suitable media. Convenientl j l Rmperty makes them sultahle, i eh the derivative is isolated from the reaction mixture as the by mleehoh routes as Well as ofahy form of hydrochloride, from which the various bases and other y p tablets, E P fl absol'Ptloh of these salts may be obtained by suitable means such as ion expounds when used medlcmally 1S obtamed' change or ion interaction. This class of compounds read- These novel types of compounds have been found Slut ily forms quaternary salts by treatment of the bases with able for the symptomatic relief of certain types of neuraldesired alkyl ha1ides gia, rheumatoid and arthritic disjorders and in h h The second class of 'saccharin derivatives (Formula a e h hound to PosseSS Varying degrees of ahhhlsta' 1-(b)) are obtained by reacting equimolecular quantities mlmc h of sodium saccharide with the desired dialkylaminoalkyl F E Y 1t 15 a besle obleet of t Preseht mvehhoh (or heterocyclic alkyl) halide in a polar solvent such as to provlde novel organic compounds and me for the dimethylformamide. The free bases are obtained directly Preparatlon e by this reaction and may then be converted to the desired h obleet 18 to P K hovel eehlpouhds e 4 simple salts or quaternary salts by neutralization or treatacterlzed by chemotherapeutic or medicinal propert es meat with appropriate ,1 halides P q l y by ahalgesleehd ahhhlsmmlmc Physio The third class of saccharin derivatives (Formula 10816211 aetlvlty m the mammaheh speeles' 1(0)) are obtained by reaction of equimolecular quan- Another Specific object to P i novel compounds tities of pseudo-saccharin chloride with the desired dialkylnamely, and saeehahh dehvahves, the Parent bases aminoalkyl (or heterocyclic alkyl) amine in a suitable imple salts and quaternary salts thereof. medium such as acetone or benzene. These compounds equally Important f l of the Invention to are obtained from the reaction mixture as the hydrochlovlde methods of syntheslzlhg the novel compounds ride salts which may be converted into the base, other ferred to m the foregomg p g simple salts, or may be quaternized as desired.

These and other Submemate ohlects and the manner Following are particularized examples of the general Whleh they are aeeomphshed W111 become apparent synthesizing processes described above--and specific resultthose conversant with the art from the following descnping members the novel general classes of compounds tion of the general types of novel compounds discovered discovered and certain specific examples of particular members there- EXAMPLE I of as well as general and specific methods of their synthesis. N-diethylaminoethyl saccharz'n Generally Stated the novel compounds embraced by The synthesizing reaction for the preparation of this :3: g gfi gg gg gg gigzi i i gig z i i gg 2: compound is illustrated by the following equation: carbon adjacent to the imide nitrogen, coupled through an oxygen ether linkage or an amino nitrogen linkage, o and forming suitable simple or quaternary salts of the bases thus obtained. so, cm

The types of compounds discovered are specifically illustrated by Formulae 1(a), 1(b) and 1(0) which follow: I U2H5 /R N-CiH4'-N 0-(CHa),N 0 can,

R R 0 In carrying out the synthesis indicated by this equation, 51 grams (0.25 mole) of sodium saccharide was dissolved R in m1. of diinethylfor'man ide and the solution rem) 1(0) fluxed for 3 hours with 33 grams of diethylaminoe'thyl chloride. Separation of sodium chloride was evident after a few minutes and the reaction was essentially complete in 3 hours. The reaction mixture was then filtered to remove the salt formed and the dimethylformamide removed from the filtrate under reduced pressure. Finally, the resulting oil was filtered through glass wool and distilled in vacuo and a yield of 55 grams of the free base was obtained. The substance solidified in the receiver and had a melting point of 61-63 C. and boiled at 144- 150 C. at a pressure of 0.06 mm.

The hydrochloride On treatment of the free base dissolved in methanol or ethanol with a saturated solution of HCl in ethanol and precipitation with ether, the hydrochloride was obtained. It was characterized by a melting point 217- 218 C. and a chloride ion content of 11.25%. The theoretically predicted chloride ion content was 11.12%.

The methiodide The free base, dissolved in anhydrous acetone and treated with an excess of methyl iodide, upon standing for several hours yielded the methiodide, which had a melting point of 199-200" C. The iodide content found was 30.04% which compares very closely to the theoretical iodide content, which is 29.91%.

EXAMPLE II N-morpholinoethyl saccharin In the manner described under Example I, the N-morpholinoethyl derivative was obtained in 80% yield of the free base when the reaction was run in 0.25 molar quantity. This substance had a boiling point of 180- 184 C. at 0.1 mm. pressure and a melting point of 103-l04 C.

The hydrochloride Conversion to the hydrochloride was eflected in the same manner as outlined in Example I and yielded the salt with a melting point of 236 C. The analysis for chloride ion content gave a value of 10.76% which checks closely with the theoretical value of 10.65%.

The methiodide Conversion to the methiodide was effected in anhydrous methanol by means of an excess quantity of methyl iodide. This quaternary salt had a melting point of 259-260 C. and iodide ion was found to be present in the amount of 29.36% as compared to 28.96% calculated theoretically for this salt.

EXAMPLE III Dimethylaminoethyl pseudo-saccharin ether The synthesizing reaction for the preparation of this compound is illustrated by the following equation:

N so/ In carrying out the synthesis indicated by this equation, 40 grams (0.2 mole) of pseudo-saccharin chloride was dissolved in 250 ml. of anhydrous acetone with gentle heating. After solution had been effected, 18 grams (0.2 mole) of dimethylaminoethyl alcohol dissolved in 50 ml. of acetone was slowly added. The reaction was instantaneous and exothermic. The mixture, after re-v fluxing gently for /2 hour, was cooled and filtered and Melting Percent chloride ion Example Compound Point,

Actual Theoretical IV Piperidinoethyl pseudo- -151 10. 33 10. 72

saceharln ether (hydro chloride) V Pyrrolidinoethyl 151-152 11.46 11.19

pseudo-saccharin ether (hydrochloride). VI Beta-di-n-butylamino- 135437 9. 30 9. 16

propyl pseudo-saccharin ether (hydrochloride).

EXAMPLE VII I C-dz'methylaminopropyl amino pseudo-saccharin The synthesizing reaction for the preparation of this compound is illustrated by the following equation:

In carrying out this synthesis, 40 grams (0.2 mole) of pseudo-saccharin chloride was dissolved with gentle heating in 250 m1. of anhydrous acetone. After solution was complete, 20.4 grams (0.2 mole) of 3-dimethylaminopropyl amine dissolved in 50 ml. of acetone was added rapidly but cautiously. An exothermic reaction ensued and the product precipitated out in the form of colorless crystals. The mixture was refluxed gently for an additional /2 hour, cooled, filtered and washed with anhydrous acetone and then ether and dried. The resulting compound had a melting point of 206-207 C. and analysis thereof showed a chloride ion content of 11.67% which is exactly the value arrived at by theoretical calculations.

EXAMPLE VIII C-diethylaminoethylamino pseudo-saccharin This compound, prepared by means of a reaction analogous to that described in Example II using the appropriate amine, on standing 4 days yielded a crystalline product which on filtering, washing with acetone and ether, and drying, had a melting point of 166 C. and a chloride ion content (11.18%) extremely close to the theoretical value (11.16%).

EXAMPLE IX Y C-rrrorpholinoethylamino pseudo-saccharin this discovery in the symptomatic treatment of certain diseases has already been mentioned hereinabove. The O-saccharins have been found to be of particular value as analgesics in the treatment of neuralgia, arthritic and various related rheumatoid disorders. To this end a recommended effective dosage is 250 to 330 milligrams given orally or 50 milligrams by injection, in either case once a day.

The N-saccharins are similarly etfective administered orally, twice daily in 60 milligram dosages.

From the foregoing description of novel classes of compounds, particular exemplary members of the classes and general and specific methods of synthesizing same, it will be understood that on the basis of the discovery and knowledge disclosed herein other specific compounds have been and can be made and variations in the methods of synthesis resorted to. Therefore specific compounds and methods disclosed herein are to be considered in all respects as illustrative and not restrictive, the scope of the discovery being indicated by the appended claims rather than by the foregoing description, and all specific compounds and variations in method which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

What is claimed and desired to be secured by the United States Letters Patent is:

1. As novel compositions of matter, the N- and O- saccharin derivatives taken from the group consisting of where x represents a number from 2 to 6, and

is taken from the group consisting of the dialkylamino having 1 to 6 carbon atoms in each alkyl chain and the heterocyclic ring systems of pyrrolidine, morpholine and piperidi'ne.

2. As novel compositions of matter the saccharin derivatives having the formula where, in said formula, x is 2 and R is methyl.

3. As novel compositions of matter, the saccharin derivative having the formula namely, N diethylaminoethyl saccharin.

4. As novel compositions of matter, the hydrochloride salt of the saccharin derivative having the formula Ci CHa namely, dimethylaminoethyl pseudo-saccharin ether.

5. As novel compositions of matter, the sacchari'n derivative having the formula References Cited in the file of this patent UNITED STATES PATENTS 2,538,645 Hamilton Jan. 16, 1951 

1. AS NOVEL COMPOSITIONS OF MATTER, THE N- AND OSACCHARIN DERIVATIVES TAKEN FROM THE GROUP CONSISTING OF
 6. THE METHOD OF PREPARING SACCHARIN DERIVATIVES COMPRISED IN REACTING SODIUM SACCHARIDE WITH AN ALKYL HALIDE SELECTED FROM THE GROUP CONSISTING OF DIALKYLAMINOALKYL AND HETEROCYCLIC ALKYL HALIDES IN A POLAR SOLVENT. 